Polymer particles of size in the range of few nanometers to several hundred micrometers have been of interest as delivery vehicles for pharmaceutical and biotechnology products. Several products based on this technology have been approved by the USFDA for use in humans. The particles are known by several names including microparticles, microspheres and nanoparticles. These particles can contain dissolved or dispersed active drug molecules for prolonged delivery to the body. Typically, the drug is dispersed in the particles during their formation. The drug-polymer matrix in the form of particles can be injected at various locations in the body. The particles are typically prepared from biodegradable polymers. As the particles slowly dissolve, they release the active medicament for absorption into the body. This can allow for active levels of the medicament in the body for as long as 3 months following a single injection.
The particles can also be used without an active ingredient incorporated in them. In such a case, the particles act as a medical device. Examples of such devices can cause arterial embolism to kill cells, a tissue, etc. or elicit an immune reaction from the body.
Microspheres have can be prepared by a variety of methods. These methods rely on the use of techniques such as precipitation or co-precipitation, forming an emulsion by rapid stirring or sonication in mutually immiscible liquids. Some other methods also use a nozzle spray to atomize the particle forming agent in a solution form in a suitable solvent. In all of the methods involving a particle forming agent dissolved in the particle forming solvent, the droplets of the particle forming solution are added to another solution called as the hardening solution. The hardening solution contains ingredients such as surfactants or chemical reactants that cause the particles to harden either by loss of solvent or by a chemical reaction resulting in formation of a new material.
In the methods involving bulk sonication, the polymer forming the particle is dissolved in a suitable first solvent and this solution is added to the second solvent in which the first solvent is not soluble. This is followed by either bath sonication or tip sonication that results in a fine dispersion of the polymer solution. In this method, either a sonication tip is dipped in the solutions or the solutions are added to a sonication bath This method has the drawback of applying sonication energy to the entire system repeatedly, resulting the formation of small microspheres in the range of less than one micron to about 20 microns. However, this method also results in the formation of microspheres of highly variable particle sizes which is not desirable.
In the spray based methods, the polymer solution is typically sprayed as a fine mist in to a chamber where the particles may dry very quickly (spray drying) or the droplets may drop in a second solvent and be stirred until the first solvent evaporates, leaving behind the solid particles. This method involves application of pressure to force the polymer solution through the nozzle and once again results in a large particle size distribution as indicated by a high relative standard deviation in the size of the microparticles. Yet another disadvantage of this method is that it cannot produce particles of larger than about 50 micrometers in diameter.
In one variation of the nozzle spray method, the polymer solution is pumped through a small orifice. The orifice is simultaneously subjected to shaking using an acoustic type wave. This method dislodges the droplets from the nozzle at a regular rate that depends on the frequency of the acoustic wave, thereby resulting in the formation of a single droplet at a time. This allows for a tight control of the droplet size, and results in the formation of particles with a very tight size distribution. This method, however, suffers from several disadvantages. This method involves application of high pressure for pumping the solution through the orifice. This limits the rate at which the solution can be pumped and becomes difficult to sustain when viscosity values of the polymer solution increase beyond a certain limit. Therefore, this method is generally applicable to relatively dilute polymer solutions at a small flow rates. Another disadvantage of this method is that it relies on the formation of one droplet at a time, thereby limiting the scalability of the process. Yet another disadvantage of this method is that it cannot produce particles with size higher than 100 microns. See, for example, U.S. Pat. No. 6,669,961.
Additional methods of preparing microparticles include the use of homogenizers or intensive stirring in order to disperse the polymer solution in a hardening solution. Additionally, the polymer solution may be sprayed from a nozzle or a similar device followed by drying of the particles in air. Several publications have outlined the details of these methods (e.g. Journal of Controlled Release, 90 (2003), pages 261-280; Journal of Controlled Release 106 (2005) pages 62-75). There are at least two disadvantages associated with these methods. First, the particle size range covers mostly smaller sizes, ranging from less than one micron to about 50 microns. Second, none of the methods described previously are easily scalable at a manufacturing scale to produce large amount of particles. The present invention addresses these and other disadvantages.